Pipex Pharmaceuticals’ Oral TRIMESTA Initiates Enrollment of Phase II/III Clinical Trial for Multiple Sclerosis
We are developing Trimesta™ as an oral, immunomodulatory and anti-inflammatory agent for the North American market. Estriol has been approved and marketed throughout Europe and Asia as a mild estrogenic agent for over 40 years for the treatment of post-menopausal hot flashes. Estriol is an important endogenous hormone that is produced in the placenta by women during pregnancy. Maternal levels of estriol increase in a linear fashion throughout the third trimester of pregnancy until birth, whereupon they abruptly fall to near zero. Our scientific inventor of TRIMESTA™ is a leading authority on the role that estriol plays in affording immunologic privilege to the fetus so as to prevent its rejection by the mother. It is a widely observed phenomenon that pregnant women with Th1-mediated autoimmune diseases (such as multiple sclerosis) experience high rates of spontaneous remission during pregnancy (especially in the third trimester) as well as high rates of relapse during the post-partum period (especially in the three-month post-partum period). Based upon these insights, the inventor of TRIMESTA™ has conducted initial clinical trials of TRIMESTA™ in non-pregnant female multiple sclerosis patients to determine safety and efficacy.
Pregnancy and MS
Doctors have known for decades that women often experience a sharp drop in MS disease symptoms during the course of pregnancy, specifically in the third trimester when the levels of estriol is being produced at their highest level by the placenta. The list of autoimmune diseases that improve during pregnancy includes:
· multiple sclerosis,
· rheumatoid arthritis,
· juvenile rheumatoid arthirits,
· ankylosing spondylitis with peripheral arthritis
· psoriatic arthritis.
A landmark clinical study published in the New England Journal of Medicine, known as the PRIMS study (Pregnancy in Multiple Sclerosis) followed 254 women with MS during 269 pregnancies and for up to one year after delivery. The PRIMS study demonstrated that relapse rates were significantly reduced by 71 percent (p<0.001) through the third trimester of pregnancy from pre-baseline levels and relapse rates then increased by 120 percent (p<0.001) during the first three months postpartum before returning to pre-pregnancy rates (3).
About Relapsing-Remitting Multiple Sclerosis (MS)
Current Therapies for Relapsing-Remitting MS.
We are developing TRIMESTA™ as an oral immunomodulatory therapy for female relapsing-remitting MS patients that can be used either alone or in combination with other agents or during the post-partum period following pregnancy. There are currently five FDA-approved first line therapies for the treatment of relapsing-remitting multiple sclerosis: Betaseron®, Rebif®, Avonex® and Copaxone®. These therapies provide only a modest benefit for patients with relapsing-remitting MS and therefore serve to only delay progression of the disease. All of these drugs require frequent (daily to weekly) injections on an ongoing basis and are associated with unpleasant side effects (such as flu-like symptoms), high rates of non-compliance among users, and eventual loss of efficacy due to the appearance of resistance in approximately 30% of patients. An estimated two-thirds of MS patients are women.
Previous Phase II Clinical Trial Results of Trimesta™ in Relapsing-Remitting MS
Trimesta™ has completed an initial 10-patient, 16-month, single-agent, crossover, phase II clinical trial in the U.S. for the treatment of MS. The results of this proof of concept study has led us to initiate a confirmatory efficacy study in 2007.
Decrease in Volume and Number of Myelin Lesions
In the relapsing-remitting MS patient group, the total volume and number of pathogenic gadolinium enhancing myelin lesions (an established neuroimaging measurement of disease activity in MS) decreased during the treatment period as compared to a six-month pre-treatment baseline period. The median total enhancing lesion volumes decreased by 79% (p=0.02) and the number of lesions decreased by 82% (p=0.09) within the first three months of treatment with Trimesta™. Over the next three months, lesion volumes decreased by 82% (p=0.02) and the number of lesions decreased by 82% (p=0.02) compared to baseline. During a three-month re-treatment phase of this clinical trial, relapsing-remitting MS patients again showed a decrease in enhancing lesion volumes (88%) (p=0.008) and a decrease in the number of lesions (48%) (p=0.04) compared to baseline 8,9.
Improvement in Cognitive Testing Scores
During this phase II clinical trial, a 14 percent improvement in Paced Auditory Serial Addition Test (“PASAT”) cognitive testing scores (p=0.04) was observed in these MS patients at six months of therapy. PASAT is a routine cognitive test performed in patients with a wide variety of neuropsychological disorders such as MS. The PASAT scores were expressed as a mean percent change from baseline and were significantly improved in the relapsing-remitting group.
About the Phase II/III Clinical Trial
TRIMESTA is currently the subject of a double-blind, placebo-controlled phase II/III clinical trial that will take place at seven sites in the U.S., enrolling up to 150 female MS patients. Investigators will administer TRIMESTA to women between the ages of 18-50 who have been recently diagnosed with relapsing-remitting MS. TRIMESTA will be given in combination with subcutaneously injected Copaxone®, a standard treatment for MS. The team is evaluating effects of the treatment combination on relapse rates using several clinical and magnetic resonance imaging measures of disability progression.
This clinical trial has received a $5 million grant from the USA National Multiple Sclerosis Society (NMSS) in partnership with the National MS Society’s Southern California chapter, with support from the National Institutes of Health (NIH).
The study sites include
1. University of California, Los Angeles (UCLA),
2. Ohio State University (OSU),
3. Rutgers University (UMDNJ),
4. Washington University,
5. St. Louis, University of Chicago,
6. University of Utah
7. University of Texas, Southwestern Medical Center.
For further information on this Phase II/III clinical trial, please visit www.clinicaltrials.gov/TRIMESTA.
Market Opportunity Multiple Sclerosis
About Pipex Pharmaceuticals, Inc
Pipex Pharmaceuticals, Inc. a specialty pharmaceutical company developing innovative late-stage drug candidates for the treatment of neurologic and fibrotic diseases, announced today that TRIMESTA (oral estriol), its proprietary therapy for multiple sclerosis (MS) has entered a multi-center, Phase II/III clinical trial for the treatment of women with relapsing-remitting MS. This clinical trial has received a $5 million grant from the National Multiple Sclerosis Society (NMSS) in partnership with the National MS Society’s Southern California chapter, with support from the National Institutes of Health (NIH).
About Multiple Sclerosis (MS)
MS is a chronic, usually progressive disease of the central nervous system in which the immune system attacks and destroys the structure, and therefore degrades the function, of nerve cells. Approximately 2.5 million individuals have MS, and virtually every hour someone is newly diagnosed. Most are between the ages of 20 and 50, and women are affected two to three times more often than men.
According to the US National MS Society, the economic cost of care for MS patients in the United States including medical and non-medical care, production losses, and informal care exceeds $23 billion annually, or more than $57,000 per U.S. patient per year. Complications from MS may make it harder for people to work and may interfere with their ability to perform common, daily activities. During 2006, combined sales estimates of FDA-approved injectable MS therapies, which include Avonex®, Betaseron®, Copaxone®, and Rebif®, totalled approximately $5.0 billion.
For most people with MS, the disease slowly progresses with a series of unpredictable flare-ups, also called relapses or exacerbations. But for some, the progression of the disease is rapid. Relapses often lead to increasing disabilities such as walking impairment, muscle weakness or speech or vision impairments.
Based upon the observations of our clinical investigators of mood-elevating benefits of Trimesta™ and the dramatic decline of estriol levels immediately post-partum, we also intend to commence a phase II/III trial of Trimesta™ for the treatment of post-partum depression.
Market Opportunities for Trimesta™ Post-partum Depression
Postpartum depression is considered to be a major depressive episode that may be associated with anxiety, persistent depression, irritable mood, or prolonged anxiety. It presents with typical depression symptoms, which can include poor concentration, problems with memory, difficulty with decision-making, irritability, decreased appetite, loss of sleep, loss of pleasure in usual daily activities, low self-esteem, negative thinking, worrying, persistent sadness, helplessness, and feelings of hopelessness. Another aspect of postpartum depression is the mother’s feeling of significant impairment or inability to care for her newborn baby or herself. The mother may also experience difficulty socializing. Some suggest such problems arise as the mother tries to adjust to the realities and demands of her new baby. Recent research also suggests that delivery of the fetus and expulsion of the placenta results in an abrupt decrease in levels of hormones such as estriol, and that these decreasing hormone levels are responsible for postpartum depression.
The difference between postpartum “blues” (also referred to as “baby blues”) and postpartum depression is that postpartum blues is short-lived and ends without treatment in a short period of time. It is estimated that the postpartum blues affects 50% of all births and postpartum depression affects 25% of all births.